tbuckley/cabot-search huggingface dataset:
Engaging a national-scale cohort of smart thermometer users in participatory surveillance
Authors: Yi-Ju Tseng, Karen L. Olson, Danielle Bloch, Kenneth D. Mandl
Journal: npj Digital Medicine (2023)

Abstract Participatory surveillance systems crowdsource individual reports to rapidly assess population health phenomena. The value of these systems increases when more people join and persistently contribute. We examine the level of and factors associated with engagement in participatory surveillance among a retrospective, national-scale cohort of individuals using smartphone-connected thermometers with a companion app that allows them to report demographic and symptom information. Between January 1, 2020 and October 29, 2022, 1,325,845 participants took 20,617,435 temperature readings, yielding 3,529,377 episodes of consecutive readings. There were 1,735,805 (49.2%) episodes with self-reported symptoms (including reports of no symptoms). Compared to before the pandemic, participants were more likely to report their symptoms during pandemic waves, especially after the winter wave began (September 13, 2020) (OR across pandemic periods range from 3.0 to 4.0). Further, symptoms were more likely to be reported during febrile episodes (OR = 2.6, 95% CI = 2.6–2.6), and for new participants, during their first episode (OR = 2.4, 95% CI = 2.4–2.5). Compared with participants aged 50–65 years old, participants over 65 years were less likely to report their symptoms (OR = 0.3, 95% CI = 0.3–0.3). Participants in a household with both adults and children (OR = 1.6 [1.6–1.7]) were more likely to report symptoms. We find that the use of smart thermometers with companion apps facilitates the collection of data on a large, national scale, and provides real time insight into transmissible disease phenomena. Nearly half of individuals using these devices are willing to report their symptoms after taking their temperature, although participation varies among individuals and over pandemic stages.
Detection, mechanisms, and therapeutic implications of oncometabolites
Authors: Ying Cai, Zhibo Wang, Sifan Guo, Chunsheng Lin, Hong Yao, Qiang Yang, Yan Wang, Xiaodan Yu, Xiaowen He, Wanying Sun, Shi Qiu, Yu Guo, Songqi Tang, Yiqiang Xie, Aihua Zhang
Journal: Trends in Endocrinology and Metabolism (2023)
Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL
Authors: Shawn H.R. Lee, Emily Ashcraft, Wenjian Yang, Kathryn G. Roberts, Yoshihiro Gocho, Lauren Rowland, Hiroto Inaba, Seth E. Karol, Sima Jeha, Kristine R. Crews, Charles G. Mullighan, Mary V. Relling, William E. Evans, Cheng Cheng, Jun J. Yang, Ching-Hon Pui
Journal: Journal of Clinical Oncology (2023)

PURPOSE High hyperdiploidy, the largest and favorable subtype of childhood ALL, exhibits significant biological and prognostic heterogeneity. However, factors contributing to the varied treatment response and the optimal definition of hyperdiploidy remain uncertain. METHODS We analyzed outcomes of patients treated on two consecutive frontline ALL protocols, using six different definitions of hyperdiploidy: chromosome number 51-67 (Chr51-67); DNA index (DI; DI1.16-1.6); United Kingdom ALL study group low-risk hyperdiploid, either trisomy of chromosomes 17 and 18 or +17 or +18 in the absence of +5 and +20; single trisomy of chromosome 18; double trisomy of chromosomes 4 and 10; and triple trisomy (TT) of chromosomes 4, 10, and 17. Additionally, we characterized ALL ex vivo pharmacotypes across eight main cytotoxic drugs. RESULTS Among 1,096 patients analyzed, 915 had B-ALL and 634 had pharmacotyping performed. In univariate analysis, TT emerged as the most favorable criterion for event-free survival (EFS; 10-year EFS, 97.3% v 86.8%; P = .0003) and cumulative incidence of relapse (CIR; 10-year CIR, 1.4% v 8.8%; P = .002) compared with the remaining B-ALL. In multivariable analysis, accounting for patient numbers using the akaike information criterion (AIC), DI1.16-1.6 was the most favorable criterion, exhibiting the best AIC for both EFS (hazard ratio [HR], 0.45; 95% CI, 0.23 to 0.88) and CIR (HR, 0.45; 95% CI, 0.21 to 0.99). Hyperdiploidy and subgroups with favorable prognoses exhibited notable sensitivities to asparaginase and mercaptopurine. Specifically, asparaginase sensitivity was associated with trisomy of chromosomes 16 and 17, whereas mercaptopurine sensitivity was linked to gains of chromosomes 14 and 17. CONCLUSION Among different definitions of hyperdiploid ALL, DI is optimal based on independent prognostic impact and also the large proportion of low-risk patients identified. Hyperdiploid ALL exhibited particular sensitivities to asparaginase and mercaptopurine, with chromosome-specific associations.
Effect of Postmenopausal Hormone Therapy on Glucose Regulation in Women With Type 1 or Type 2 Diabetes: A Systematic Review and Meta-analysis
Authors: Esther M. Speksnijder, Gaby V. ten Noever de Brauw, Arjan Malekzadeh, Peter H. Bisschop, Dirk Jan Stenvers, Sarah E. Siegelaar
Journal: Diabetes Care (2023)

BACKGROUND Blood glucose regulation in women with diabetes may change during and after menopause, which could be attributed, in part, to decreased estrogen levels. PURPOSE To determine the effect of postmenopausal hormone therapy (HT) on HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering drugs in women with type 1 and women with type 2 diabetes. DATA SOURCES We conducted a systematic search of MEDLINE, Embase, Scopus, the Cochrane Library, and the ClinicalTrials.gov registry to identify randomized controlled trials (RCTs). STUDY SELECTION We selected RCTs on the effect of HT containing estrogen therapy in postmenopausal women (≥12 months since final menstrual period) with type 1 or type 2 diabetes. DATA EXTRACTION Data were extracted for the following outcomes: HbA1c, fasting glucose, postprandial glucose, and use of glucose-lowering medication. DATA SYNTHESIS Nineteen RCTs were included (12 parallel-group trials and 7 crossover trials), with a total of 1,412 participants, of whom 4.0% had type 1 diabetes. HT reduced HbA1c (mean difference −0.56% [95% CI −0.80, −0.31], −6.08 mmol/mol [95% CI −8.80, −3.36]) and fasting glucose (mean difference −1.15 mmol/L [95% CI −1.78, −0.51]). LIMITATIONS Of included studies, 50% were at high risk of bias. CONCLUSIONS When postmenopausal HT is considered for menopausal symptoms in women with type 2 diabetes, HT is expected to have a neutral-to-beneficial impact on glucose regulation. Evidence for the effect of postmenopausal HT in women with type 1 diabetes was limited.
In This Issue of <i>Diabetes Care</i>
Authors: Max Bingham
Journal: Diabetes Care (2023)

New Guidelines on Laboratory Measures for Diagnosis and Management of DiabetesThe Americans Diabetes Association and the American Association for Clinical Chemistry have published new guidelines on laboratory measures for the diagnosis and management of diabetes.Published simultaneously in Diabetes Care (e151; Executive Summary p. 1740) and Clinical Chemistry, the guidelines are primarily aimed at laboratory professionals and clinicians involved in diabetes care.The guidelines represent an update on previously published versions and now cover emerging technologies that are being applied in clinical applications or remain in development and thus are not yet recommended for clinical application.They cover nearly all areas involving measurement in clinical care of diabetes, and they particularly consider traditional blood glucose measurements and the more modern continuous glucose monitoring.They also take an in-depth look at glycated hemoglobin, specifically the widely used HbA 1c testing.As with all measurement approaches, the issues of accuracy, precision, and bias are considered in relation to blood glucose measurement.A notable point the guidelines raise concerns blood collection and the risk of glycolysis prior to analysis.They specifically recommend the use of citrate buffer (which is not currently available in the U.S.) to minimize glycolysis and note the wide implications this will likely have on increasing rates of diabetes detection.Other areas of consideration include ketones and urine albumin, which are widely used clinically.Noninvasive glucose monitoring, genetic testing, and measurements of autoantibodies, insulin, and C-peptide also have their place, but overall they have limited clinical applicability at present and are mainly useful currently in research applications."An evidence-based approach was used to develop recommendations for laboratory analysis in screening, diagnosis, and monitoring of diabetes," said author David B. Sacks." We hope that the information facilitates the optimum use of laboratory tests in the management of individuals with diabetes."
Comment on Haidar et al. A Randomized Crossover Trial to Compare Automated Insulin Delivery (the Artificial Pancreas) With Carbohydrate Counting or Simplified Qualitative Meal-Size Estimation in Type 1 Diabetes. Diabetes Care 2023;46:1372–1378
Authors: Julie Blervaque, Sandrine Lablanche, Hector Romero-Ugalde, Alice Adenis, Guillaume Charpentier, Pierre Yves Benhamou
Journal: Diabetes Care (2023)
Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT
Authors: Francesco Saraceni, Myriam Labopin, Anna M. Raiola, Didier Blaise, Péter Reményi, Federica Sorà, Jiri Pavlu, Stefania Bramanti, Alessandro Busca, Ana Berceanu, Giorgia Battipaglia, Giuseppe Visani, Gerard Sociè, Gesine Bug, Caterina Micò, Giorgio La Nasa, Maurizio Musso, Attilio Olivieri, Alexandros Spyridonidis, Bipin Savani, Fabio Ciceri, Arnon Nagler, Mohamad Mohty
Journal: HemaSphere (2023)

We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m 2 and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II–IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III–IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo ( P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% ( P = 0.6), 73% versus 76% ( P = 0.5), and 54% versus 53% ( P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.
Proceedings of a Workshop to Promote Community Health Worker Interventions in Nephrology
Authors: Tessa K. Novick, Lilia Cervantes, Ladan Golestaneh, Michelle Osuna, Evelyn Cruz, Luz Baqueiro, Marissa Argentina, Andrea Sandoval, Arleen Brown, Franco Reyna, Sylvia E. Rosas, Claudia Camacho, Jenny Shen
Journal: Journal of the American Society of Nephrology (2023)

ABSTRACT Latinx populations face a higher burden of kidney failure and associated negative outcomes compared with non-Latinx White populations, despite sharing a similar prevalence of CKD. Community health worker (CHW) interventions have been shown to improve outcomes for Latinx individuals, but they are largely underutilized in kidney disease. We convened a workshop of four ongoing kidney disease CHW programs to identify successes, challenges, potential solutions, and needed research to promote CHW programs for Latinx individuals with kidney disease. Key points from the workshop and recommendations for intervention and research are highlighted. Facilitators of program success included prioritizing trust-building with participants, enabling participants to determine what aspects of the intervention were needed, providing participants with tools to help themselves and others after the intervention, and taking a trauma-informed approach to relationships. Challenges included persistent systemic barriers despite successful care navigation and low recruitment and retention. Research is needed to capture the effect of CHW interventions on outcomes and to determine how to implement CHW interventions for people with kidney disease nationwide.
Sex Differences in Myocardial Histology, Gene Expression, and Myocardial Recovery in Recent-Onset Cardiomyopathy
Authors: Agnes Koczo, Anjali Rao, Randall C. Starling, Leslie T. Cooper, G. William Dec, Jeffrey D. Alexis, John Gorcsan, Charles McTiernan, Dennis M. McNamara
Journal: JACC Heart Failure (2023)
Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy
Authors: Suman Mukhopadhyay, Hsin-Yi Huang, Ziyan Lin, Michela Ranieri, Shuai Li, Soumyadip Sahu, Yingzhuo Liu, Yi Ban, Kayla Guidry, Hai Hu, Alfonso Lopez, Fiona Sherman, Yi Jer Tan, Yeuan Ting Lee, Amanda P. Armstrong, Igor Dolgalev, Priyanka Sahu, Tinghu Zhang, Wenchao Lu, Nathanael S. Gray, James G. Christensen, Tracy T. Tang, Vamsidhar Velcheti, Alireza Khodadadi-Jamayran, Kwok-Kin Wong, Benjamin G. Neel
Journal: Cancer Research (2023)

Abstract Non–small lung cancers (NSCLC) frequently (∼30%) harbor KRAS driver mutations, half of which are KRASG12C. KRAS-mutant NSCLC with comutated STK11 and/or KEAP1 is particularly refractory to conventional, targeted, and immune therapy. Development of KRASG12C inhibitors (G12Ci) provided a major therapeutic advance, but resistance still limits their efficacy. To identify genes whose deletion augments efficacy of the G12Cis adagrasib (MRTX-849) or adagrasib plus TNO155 (SHP2i), we performed genome-wide CRISPR/Cas9 screens on KRAS/STK11-mutant NSCLC lines. Recurrent, potentially targetable, synthetic lethal (SL) genes were identified, including serine–threonine kinases, tRNA-modifying and proteoglycan synthesis enzymes, and YAP/TAZ/TEAD pathway components. Several SL genes were confirmed by siRNA/shRNA experiments, and the YAP/TAZ/TEAD pathway was extensively validated in vitro and in mice. Mechanistic studies showed that G12Ci treatment induced gene expression of RHO paralogs and activators, increased RHOA activation, and evoked ROCK-dependent nuclear translocation of YAP. Mice and patients with acquired G12Ci- or G12Ci/SHP2i-resistant tumors showed strong overlap with SL pathways, arguing for the relevance of the screen results. These findings provide a landscape of potential targets for future combination strategies, some of which can be tested rapidly in the clinic. Significance: Identification of synthetic lethal genes with KRASG12C using genome-wide CRISPR/Cas9 screening and credentialing of the ability of TEAD inhibition to enhance KRASG12C efficacy provides a roadmap for combination strategies. See related commentary by Johnson and Haigis, p. 4005
Combinatorial Treatment with PARP and MAPK Inhibitors Overcomes Phenotype Switch-Driven Drug Resistance in Advanced Melanoma
Authors: Lorenza P. Ferretti, Flurina Böhi, Deena M. Leslie Pedrioli, Phil F. Cheng, Elena Ferrari, Petra Baumgaertner, Abdiel Alvarado-Diaz, Federica Sella, Alessandra Cereghetti, Patrick Turko, Roni H. Wright, Katrien De Bock, Daniel E. Speiser, Roberto Ferrari, Mitchell P. Levesque, Michael O. Hottiger
Journal: Cancer Research (2023)

Abstract Metastatic melanoma is either intrinsically resistant or rapidly acquires resistance to targeted therapy treatments, such as MAPK inhibitors (MAPKi). A leading cause of resistance to targeted therapy is a dynamic transition of melanoma cells from a proliferative to a highly invasive state, a phenomenon called phenotype switching. Mechanisms regulating phenotype switching represent potential targets for improving treatment of patients with melanoma. Using a drug screen targeting chromatin regulators in patient-derived three-dimensional MAPKi-resistant melanoma cell cultures, we discovered that PARP inhibitors (PARPi) restore sensitivity to MAPKis, independent of DNA damage repair pathways. Integrated transcriptomic, proteomic, and epigenomic analyses demonstrated that PARPis induce lysosomal autophagic cell death, accompanied by enhanced mitochondrial lipid metabolism that ultimately increases antigen presentation and sensitivity to T-cell cytotoxicity. Moreover, transcriptomic and epigenetic rearrangements induced by PARP inhibition reversed epithelial–mesenchymal transition-like phenotype switching, which redirected melanoma cells toward a proliferative and MAPKi-sensitive state. The combination of PARP and MAPKis synergistically induced cancer cell death both in vitro and in vivo in patient-derived xenograft models. Therefore, this study provides a scientific rationale for treating patients with melanoma with PARPis in combination with MAPKis to abrogate acquired therapy resistance. Significance: PARP inhibitors can overcome resistance to MAPK inhibitors by activating autophagic cell death and reversing phenotype switching, suggesting that this synergistic combination could help improve the prognosis of patients with melanoma.
TP63 fusions drive multicomplex enhancer rewiring, lymphomagenesis, and EZH2 dependence
Authors: Gongwei Wu, Noriaki Yoshida, Jihe Liu, Xiaoyang Zhang, Yuan Xiong, Tayla B. Heavican-Foral, Elisa Mandato, Huiyun Liu, Geoffrey M. Nelson, Lu Yang, Renee Chen, Katherine A. Donovan, Marcus K. Jones, Mikhail Roshal, Yanming Zhang, Ran Xu, Ajit J. Nirmal, Salvia Jain, Catharine Leahy, Kristen L. Jones, Kristen E. Stevenson, Natasha Galasso, Nivetha Ganesan, Tiffany Chang, Wen-Chao Wu, Abner Louissaint, Lydie Debaize, Hojong Yoon, Paola Dal Cin, Wing C. Chan, Shannan J. Ho Sui, Samuel Y. Ng, Andrew L. Feldman, Steven M. Horwitz, Karen Adelman, Eric S. Fischer, Chun-Wei Chen, David M. Weinstock, Myles Brown
Journal: Science Translational Medicine (2023)

Gene fusions involving tumor protein p63 gene (TP63) occur in multiple T and B cell lymphomas and portend a dismal prognosis for patients. The function and mechanisms of TP63 fusions remain unclear, and there is no target therapy for patients with lymphoma harboring TP63 fusions. Here, we show that TP63 fusions act as bona fide oncogenes and are essential for fusion-positive lymphomas. Transgenic mice expressing TBL1XR1::TP63, the most common TP63 fusion, develop diverse lymphomas that recapitulate multiple human T and B cell lymphomas. Here, we identify that TP63 fusions coordinate the recruitment of two epigenetic modifying complexes, the nuclear receptor corepressor (NCoR)—histone deacetylase 3 (HDAC3) by the N-terminal TP63 fusion partner and the lysine methyltransferase 2D (KMT2D) by the C-terminal TP63 component, which are both required for fusion-dependent survival. TBL1XR1::TP63 localization at enhancers drives a unique cell state that involves up-regulation of MYC and the polycomb repressor complex 2 (PRC2) components EED and EZH2. Inhibiting EZH2 with the therapeutic agent valemetostat is highly effective at treating transgenic lymphoma murine models, xenografts, and patient-derived xenografts harboring TP63 fusions. One patient with TP63 -rearranged lymphoma showed a rapid response to valemetostat treatment. In summary, TP63 fusions link partner components that, together, coordinate multiple epigenetic complexes, resulting in therapeutic vulnerability to EZH2 inhibition.
A bioengineered trachea-like structure improves survival in a rabbit tracheal defect model
Authors: Hai Tang, Weiyan Sun, Xiucheng Liu, Qing Gao, Yi Chen, Chaoqi Xie, Weikang Lin, Jiafei Chen, Long Wang, Ziwen Fan, Lei Zhang, Yijiu Ren, Yunlang She, Yong He, Chang Chen
Journal: Science Translational Medicine (2023)

A practical strategy for engineering a trachea-like structure that could be used to repair or replace a damaged or injured trachea is an unmet need. Here, we fabricated bioengineered cartilage (BC) rings from three-dimensionally printed fibers of poly(ɛ-caprolactone) (PCL) and rabbit chondrocytes. The extracellular matrix (ECM) secreted by the chondrocytes combined with the PCL fibers formed a "concrete-rebar structure," with ECM deposited along the PCL fibers, forming a grid similar to that of native cartilage. PCL fiber-hydrogel rings were then fabricated and alternately stacked with BC rings on silicone tubes. This trachea-like structure underwent vascularization after heterotopic transplantation into rabbits for 4 weeks. The vascularized bioengineered trachea-like structure was then orthotopically transplanted by end-to-end anastomosis to native rabbit trachea after a segment of trachea had been resected. The bioengineered trachea-like structure displayed mechanical properties similar to native rabbit trachea and transmural angiogenesis between the rings. The 8-week survival rate in transplanted rabbits was 83.3%, and the respiratory rate of these animals was similar to preoperative levels. This bioengineered trachea-like structure may have potential for treating tracheal stenosis and other tracheal injuries.
Fatty Acid Oxidation Mediated by Malonyl-CoA Decarboxylase Represses Renal Cell Carcinoma Progression
Authors: Lijie Zhou, Yongbo Luo, Yuenan Liu, Youmiao Zeng, Junwei Tong, Mengting Li, Yaxin Hou, Kaixuan Du, Yabin Qi, Wenbang Pan, Yuanhao Liu, Rongli Wang, Fengyan Tian, Chaohui Gu, Ke Chen
Journal: Cancer Research (2023)

Abstract Fatty acid metabolism reprogramming is a prominent feature of clear cell renal cell carcinoma (ccRCC). Increased lipid storage supports ccRCC progression, highlighting the importance of understanding the molecular mechanisms driving altered fatty acid synthesis in tumors. Here, we identified that malonyl-CoA decarboxylase (MLYCD), a key regulator of fatty acid anabolism, was downregulated in ccRCC, and low expression correlated with poor prognosis in patients. Restoring MLYCD expression in ccRCC cells decreased the content of malonyl CoA, which blocked de novo fatty acid synthesis and promoted fatty acid translocation into mitochondria for oxidation. Inhibition of lipid droplet accumulation induced by MLYCD-mediated fatty acid oxidation disrupted endoplasmic reticulum and mitochondrial homeostasis, increased reactive oxygen species levels, and induced ferroptosis. Moreover, overexpressing MLYCD reduced tumor growth and reversed resistance to sunitinib in vitro and in vivo. Mechanistically, HIF2α inhibited MLYCD translation by upregulating expression of eIF4G3 microexons. Together, this study demonstrates that fatty acid catabolism mediated by MLYCD disrupts lipid homeostasis to repress ccRCC progression. Activating MLYCD-mediated fatty acid metabolism could be a promising therapeutic strategy for treating ccRCC. Significance: MLYCD deficiency facilitates fatty acid synthesis and lipid droplet accumulation to drive progression of renal cell carcinoma, indicating inducing MYLCD as a potential approach to reprogram fatty acid metabolism in kidney cancer.